1. Field of the Invention
The present invention relates to a process for making amlodipine maleate with good purity.
2. Description of the Related Arts
Calcium channel blockers (calcium antagonists) are useful in treating cardiac conditions including angina and/or hypertension. Dicarboxylate-dihydropyridine derivatives are generally known to possess calcium channel blocking activity. For example, EP 089 167 and corresponding U.S. Pat. No. 4,572,909 disclose a class of 2-amino group-3,5-dicarboxylate dihydropyridine derivatives as being useful calcium channel blockers. These patents identify that one of the most preferred compounds is 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-Methyl-1,4-dihydropyridine. This compound, which is now commonly known as amlodipine, has the following formula: 
Amlodipine exhibits good bioavailability and has a long half-life in the body. While a variety of acid addition salts are taught in these patents to be suitable, the maleate salt is identified as the most preferred acid addition salt. Examples 9, 11, 12 and 22 of EP 89167 as well as J. Med. Chem. 29, 1698 (1986) disclose the preparation of amlodipine maleate (with 1:1 molar ratio of both components) by dissolving a reaction mixture containing an in situ prepared raw amlodipine base into ethyl acetate or into ethanol and adding thereto solid maleic acid whereby the maleate salt of amlodipine precipitates. The salt is then isolated by filtration and recrystallized from ethyl acetate or from acetone/ethyl acetate 1:1 mixture.
However, the commercial product of amlodipine (NORVASC by Pfizer) uses amlodipine besylate (benzene sulfonate) and not amlodipine maleate. Indeed, subsequent patents EP 244 944 and corresponding U.S. Pat. No. 4,879,303 indicate that the besylate salt provides certain advantages over the known salts including good formulating properties. Apparently, amlodipine maleate suffered from tabletting and stability problems so as to cause a switch during development to the besylate salt. (See xe2x80x9cReview of Original NDAxe2x80x9d for NDA# 19-787 of 10.10.1990, obtainable from FDA under Freedom of Information Act). The stability and tabletting issues/causes are not publicly disclosed in the information available from the FDA.
The present invention relates to the discovery of a heretofore undisclosed impurity associated with amlodipine maleate and to a process for preventing its formation during production. Specifically, the present invention relates to a process that comprises reacting amlodipine or a pharmaceutically acceptable salt thereof with maleic acid under an acidic environment to form an amlodipine maleate product. Typically the process relates to the manufacture of an amlodipine maleate salt substantially free of amlodipine aspartate, which comprises the steps of (a) either (1) adding, continuously or portionwise, a source of amlodipine into a solution or suspension of maleic acid to form a solution, wherein the relative molar amount of maleic acid to amlodipine being added is at least 1.01:1 or (2) contacting, continuously or portionwise, a source of amlodipine with a solution or suspension of maleic acid under pH control to form a solution whereby the pH of the solution does not exceed 6.5; and (b) separating amlodipine maleate in a solid form from the solution. Further the present invention relates to a process of purification of amlodipine maleate, which comprises crystallizing or precipitating amlodipine maleate from a solution thereof wherein said solution comprises an excess of maleic acid.